Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/02—Preparation
  • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

• British Pat. No. 1,326,531 describes an elaborate bromination step to form the compounds of formula I which can then be readily reacted to replace the bromine atom by various nucleophilic atoms or groups to give 3'-nucleophilic substituted desacetoxy-cephalosporanic acid derivatives which are, or can be converted by methods known per se into, antibiotically active cephalosporanic derivatives.
• the said bromination process is effected in manner known per se of corresponding desacetoxy-3-cephem sulfoxides of the formula ##STR2## wherein R 1 and R 2 are hereinbefore defined, and separation is made of the desired 3-bromomethyl-3-cephem sulfoxides of formula I from the reaction mixture.
• This straightforward procedure does not give very satisfactory yields of the desired products, inter alia because side-reactions can take place whereby bromine is introduced into other positions than that of the 3-methyl group of the compounds of formula II, for example in the 2-position.
• the improved process of the invention for the preparation of compounds of the formula ##STR3## wherein R 1 is an acylamido group and R 2 is a group protecting the carboxy radical comprises brominating a compound of the formula ##STR4## wherein R 1 and R 2 have the above definition to obtain a mixture of compounds of the formulae ##STR5## and treating the mixture or the compound of formula III with a debrominating agent in the presence of a hydrogen donor to selectively remove the 2-bromine.
• the desired product of formula I may then be recovered by conventional means.
• the acylamido of R 1 can be any group--hitherto disclosed in the chemical literature including patent specifications or known to those skilled in the art of penicillin or cephalosporin chemistry--attached to the 6-position in natural or synthetic penicillin compounds or attached to the 7-position of natural or synthetic cephalosporin compounds.
• the acylamido group is one present in the 6 ⁇ -side chain of penicillins that can be obtained by fermentative procedures which penicillins can readily be converted into cephem sulfoxides by known methods.
• Suitable groups of R 1 are for example, phenylacetamido, phenoxyacetamido, benzamido and formamido.
• R 2 can be any group known to those skilled in the art for protecting the carboxy radical of penicillanic acid or cephalosporanic acid derivatives, but preferably R 2 is an ester group which can be readily introduced and easily removed again after the reaction has been completed.
• Suitable ester groups are, for example, straight- or branched-chain alkyls of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms or by one or two phenyl groups, which phenyl groups may themselves carry one or more substituents such as nitro and methoxy groups, and silyl groups, for example trialkylsilyl groups.
• ester groups are the methyl, t-butyl, 2-bromoethyl, 2,2,2-trichloroethyl, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, benzhydryl and trimethylsilyl groups.
• This conversion is an additional advantage of the process of the invention since it prevents loss of starting material in the form of the undesired 2-bromo-3-methyl derivative which is recycled as the starting material and this can then be used again in the improved bromination process of the invention.
• the yields of the 3-bromomethyl-3-cephem sulfoxide derivatives of formula I obtained can be improved considerably as compared with the known processes for the bromination of desacetoxy-3-cephem sulfoxides of the formula II.
• Bromination of a desacetoxy-3-cephem sulfoxide of formula II to convert the methyl group in the 3-position to a bromomethyl group can be effected with known brominating agents such as N-bromoimides or N-bromoamides.
• Suitable brominating agents are, for example, 1,3-dibromo-5,5-dimethylhydantoin and N-bromosuccinimide.
• the necessary activation of the brominating agent can be achieved by adding a free radical initiator to the reaction mixture or by irradiation of the reaction mixture with ultraviolet or visible light, e.g. electric light from a 150-500 W. lamp.
• Suitable free radical initiators are, for example, azo compounds such as azo-isobutyronitrile, and peroxides such as benzoyl peroxides.
• the reaction is preferably carried out in a suitable inert organic solvent, for example, methylene chloride or 1,2-dichloroethane.
• the reaction is advantageously carried out at a temperature between 40° and 90° C.
• the temperature of the reaction mixture is preferably between -20° and 30° C.
• the quantities of the various products in the reaction mixture can be established by HPLC analysis.
• the bromination products are first isolated in the manner described hereinbefore. Then, the content of the products and that of the starting material is determined by quantitative NMR analysis. These compounds are then used as references in the HPLC analysis to determine the quantities of the various products in the reaction mixture, before and after the debromination has been carried out.
• the reaction mixtures Before this analysis method is effected, the reaction mixtures have to be diluted to obtain concentrations suitable for this method. The values given in the Examples hereafter are always in relation to such diluted mixtures. This method of analysis has an accuracy of approximately 10%.
• the reaction mixture containing 2-bromo-3-methyl-, 2-bromo-3-bromomethyl- and 3-bromomethyl-3-cephem sulfoxides is treated with a debrominating agent in the presence of a hydrogen donor to convert the 2-bromo-3-bromomethyl compound of formula III present therein to the desired 3-bromomethyl compound of formula I, and concurrently also a 2-bromo-3-methyl-3-cephem sulfoxide back again to a starting material of formula II which can then be used again.
• a 2-bromo-3-bromomethyl-3-cephem sulfoxide of formula III present in the reaction mixture can, after separation and optional purification, by itself be treated with a debrominating agent in the presence of a hydrogen donor to convert it to a 3-bromomethyl compound of formula I.
• the debromination is preferably carried out in a suitable organic solvent, for example, acetone, acetonitrile, acetic acid, dioxane, ethyl acetate, methylene chloride, 1,2-dichloroethane, 1,2-dimethoxyethane, tetrahydrofuran, 2-methoxyethanol, propylene carbonate, N,N-dimethylacetamide, bis(2-methoxyethyl)ether or tetrahydrothiopene 1,1-dioxide.
• a suitable organic solvent for example, acetone, acetonitrile, acetic acid, dioxane, ethyl acetate, methylene chloride, 1,2-dichloroethane, 1,2-dimethoxyethane, tetrahydrofuran, 2-methoxyethanol, propylene carbonate, N,N-dimethylacetamide, bis(2-methoxyethyl)ether or tetra
• Debromination of a 2-bromo-3-bromomethyl-3-cephem sulfoxide of formula III, as such or as present in the reaction mixture in which it is formed by the bromination of a compound of formula II, --to a 3-bromomethyl-3-cephem sulfoxide of formula I can be effected by treatment in the presence of a hydrogen donor with a trivalent organic phosphorus compound or an inorganic salt as the debrominating agent.
• Suitable debrominating agents are selected from the group consisting of
• phosphites for example phenyl neopentylglycol phosphite, poly(dipropyleneglycol)phenyl phosphite, tris 25 phosphite and tris(dipropyleneglycol)phosphite;
• di- and triphosphites for example diisodecyl pentaerythritol diphosphite, tetraphenyl dipropyleneglycol diphosphite, distearyl pentaerythritol diphosphite, diphenyl didecyl (2,2,4-trimethyl-1,3-pentanediol)diphosphite, tetrakis(nonylphenyl)polypropyleneglycol diphosphite and heptakis(dipropyleneglycol)triphosphite;
• phosphinites for example lower alkyl diphenylphosphinites
• phosphines for example chlorodiphenylphosphine
• inorganic salts for example stannous chloride (SnCl 2 ), sodium sulfite (Na 2 SO 3 ) and sodium dithionite (Na 2 S 2 O 4 ).
• lower alkyl as employed herein is meant to be straight- or branched-chain alkyls of 1 to 4 carbon atoms such as methyl, ethyl, allyl and t-butyl.
• the debromination step is preferably carried out with at least an equimolar quantity of the debrominating agent in relation to the 2-bromo-3-bromomethyl compound of formula III and at ambient or somewhat lower temperatures.
• the debrominating agent is of group (h) mentioned above, the ratio between the reactants should be approximately equimolar and when the debromination agent is of groups (a) to (g), a rather substantial excess of debrominating agent can be used as well.
• Suitable debrominating agents of formula IV which may be used in the process of the invention are, for example, trimethyl phosphite, triethyl phosphite, tripropyl phosphite, triisopropyl phosphite, tributyl phosphite, triisobutyl phosphite, triamyl phosphite, trioctyl phosphite, triisooctyl phosphite, tris(2-ethylhexyl)phosphite, tridecyl phosphite, triisodecyl phosphite, trineodecyl phosphite, trilauryl phosphite, tristearyl phosphite, triallyl phosphite, tris(2-chloroethyl)phosphite, triphenyl phosphite, tri
• Suitable phosphonites which may be used in the process of the invention are, for example, dimethyl phenylphosphonite, diethyl phenylphosphonite and di(t-butyl)phenylphosphonite.
• Suitable phosphinites are, for example, methyl diphenylphosphinite and ethyl diphenylphosphinite.
• the debromination of inter alia the 2-bromo-3-bromomethyl-3-cephem sulfoxides of formula III should be carried out in the presence of a hydrogen donor which donor is usually already present in the reaction medium, for example in the form of water, etc. But in some cases it may be advantageous to add a hydrogen donor such as water, a lower alkanol such as methanol, or a carboxylic acid such as acetic acid to the reaction medium.
• a hydrogen donor such as water, a lower alkanol such as methanol, or a carboxylic acid such as acetic acid
• 3-cephem sulfoxides of formula III are new compounds such as the compounds conforming to that formula obtained as intermediate products in Example I(c), VI(d) and VIII(d), namely t-butyl 7-benzamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylate 1-oxide, 2,2,2-trichloroethyl 7-formamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylate 1-oxide and methyl 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide.
• the starting materials of formula II which are brominated are known products or can be prepared by methods known per se.
• methods known per se as used in this specification is meant methods heretofore used or described in the chemical literature.
• the compound thus obtained was used as a reference in the following HPLC analysis.
• 248.1 mg of the product obtained in Example I(c) (with a purity of 78% according to quantitative NMR analysis) were dissolved in 10 ml of acetone and 0.05 ml of acetic acid was added to the solution.
• 0.2 ml of trimethyl phosphite were added thereto and the mixture was held in the ice bath for another 10 minutes and then acetone was added until the volume of the mixture was exactly 25 ml. 5 ml of this solution were diluted once more with acetone to 25 ml and 5 ml of the thus obtained solution were used in the HPLC analysis.
• the solution contained per ml: 1.0 ⁇ 10 -3 mmoles of t-butyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide, 0.17 ⁇ 10 -3 mmoles of t-butyl 2-bromo-3-methyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide and 0.66 ⁇ 10 -3 mmoles of t-butyl 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide.
• the starting material in the bromination process i.e. t-butyl 7-phenylacetamido-3-methyl-3-cephem-4-carboxylate 1-oxide could not be detected anymore in the reaction mixture.
• the reference 2-bromo-3-bromomethyl compound in the above HPLC analysis was prepared as follows: To a solution of 4.6 g (9.5 mmoles) of t-butyl 2-bromo-7-phenylacetamido-3-methyl-3-cephem-4-carboxylate 1-oxide in 350 ml of methylene chloride cooled in ice and irradiated with a 150 W tungsten lamp were added in portions over a period of 105 minutes 3.05 g (17.1 mmoles) of N-bromosuccinimide. After the addition was completed, the irradiation was continued for another hour and the orange-colored solution was concentrated to dryness by evaporation at low temperature.
• the reference compound II in this HPLC analysis namely 2-bromoethyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide, was prepared as follows: To an ice-cooled solution of 2.28 g (5 mmoles) of 2-bromoethyl 7-phenylacetamido-3-methyl-3-cephem-4-carboxylate 1-oxide in 20 ml of 1,2-dichloroethane and 20 ml of acetic acid which was held under nitrogen and was irradiated with a 150 W tungsten lamp, 1.42 g (8 mmoles) of N-bromosuccinimide were added in portions over a period of 2 hours.
• the reference compound IV was not available. Accordingly, although a quantitative increase of the concentration of compound II during the debromination process could be established, it was not possible to correlate this with a corresponding quantitative decrease of the concentration of compound IV.
• the reference compound IV in the HPLC analysis was prepared as follows: To a solution of 4.71 g (15 mmoles) of t-butyl 7-formamido-3-methyl-3-cephem-4-carboxylate 1-oxide in 250 ml of methylene chloride, cooled in ice and irradiated with a 150 W tungsten lamp, 3.15 ml (22.5 mmoles) of triethylamine and 2.7 g (15 mmoles) of N-bromosuccinimide were added. After irradiation for 10 minutes, the starting material had disappeared completely according to TLC and the dark-brown solution thus obtained was washed twice with dilute hydrochloric acid solution (pH 1) and then twice with water.
• pH 1 dilute hydrochloric acid solution
• the reference compound IV in the HPLC analysis was prepared as follows: 1 g (1.8 mmol) of t-butyl 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide [prepared by the procedure of Step C of Example II] was dissolved in 15 ml of trifluoroacetic acid and after standing for 15 minutes at room temperature, the solution was evaporated to dryness. The residue was dissolved in methylene chloride and the solution was again evaporated to dryness.
• Example XV The procedure of Example XV was repeated using t-butyl 7-benzamido-3-methyl-3-cephem-4-carboxylate 1-oxide as a starting material.
• the results of the following debromination procedure are summarized in the following Table.
• Example XVII The procedure of Example XVII was repeated but t-butyl 7-benzamido-3-methyl-3-cephem-4-carboxylate 1-oxide was used as the starting material.
• the results of the HPLC analysis of the debromination process in still some other solvents are listed below.
• the reaction mixture obtained in Step A was subjected to a series of debromination reactions with the phosphites mentioned below.
• the trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide thus prepared was first converted into the corresponding methyl ester by adding each of the reaction mixtures obtained after the series of debromination reactions was carried out, to an excess of a solution of diazomethane in diethyl ether containing some methanol.
• the excess diazomethane was destroyed with acetic acid and the solvent was evaporated.
• the residue was dissolved in acetone and the volume of the solution was adjusted to 250 ml. This solution was then used in the HPLC analysis as described previously.
• Trimethylsilyl 7-phenylacetamido-3-methyl-3-cephem-4-carboxylate 1-oxide was brominated by the process of Step A of Example II using 1,2-dichloroethane as a solvent.
• the reaction mixture was subjected to a debromination reaction by the procedure of Step B of Example II.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Cephalosporin Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=10396311

Family Applications (1)

Country Status (14)

Cited By (4)

Citations (1)

Family Cites Families (2)

• 1978
  • 1978-08-30 US US05/937,989 patent/US4182870A/en not_active Expired - Lifetime
  • 1978-09-06 NO NO783042A patent/NO155010C/no unknown
  • 1978-09-06 AU AU39584/78A patent/AU519710B2/en not_active Expired
  • 1978-09-06 DK DK394978A patent/DK159784C/da active
  • 1978-09-06 DE DE7878200174T patent/DE2860746D1/de not_active Expired
  • 1978-09-06 IE IE1803/78A patent/IE47394B1/en not_active IP Right Cessation
  • 1978-09-06 EP EP78200174A patent/EP0001149B1/en not_active Expired
  • 1978-09-06 IL IL7855522A patent/IL55522A0/xx not_active IP Right Cessation
  • 1978-09-06 AT AT0643378A patent/AT366695B/de not_active IP Right Cessation
  • 1978-09-06 HU HU78GI282A patent/HU174576B/hu not_active IP Right Cessation
  • 1978-09-06 FI FI782731A patent/FI66875C/fi not_active IP Right Cessation
  • 1978-09-06 JP JP10950878A patent/JPS5448793A/ja active Granted
  • 1978-09-06 IT IT69053/78A patent/IT1108678B/it active
  • 1978-09-06 ES ES473127A patent/ES473127A1/es not_active Expired

Patent Citations (1)

Also Published As

Similar Documents